Chewable composition for rapid buccal absorption

ABSTRACT

The present document describes a buccal delivery dosage form for administration of an active ingredient, including pharmaceutically, pharmacologically, or biologically active ingredients, in the mouth of a subject. The buccal delivery dosage form by-passes the gastrointestinal tract metabolism. The buccal delivery dosage form may comprise chemical permeation enhancers, excipients, texture modulators, and active ingredients.

The subject matter disclosed generally relates to a chewable vehicle forabsorption or uptake of active molecules in the mouth.

Digestion is the mechanical and biochemical breaking down of food andactive ingredients into a smaller component that can be absorbed by thebody. Bioavailability of small molecules and active ingredients isprovided by their routes of absorption. Usually, the most common routeto absorb food is the gastrointestinal tract (gut). The food breakdownbegins with mastication followed by the transit time in the stomach. Thegastric juice present in the stomach helps the degradation of food withacidity over a range of pH. In fact, the pH of an empty stomach isreally acid (pH of about 1 to about 2) with an empty stomach and thetransit time is in the vicinity of 30 minutes, whereas the pH is about 4after a meal, with a transit time of 120 minutes. Following stomachtransit, smaller components are headed to the gut. However, in the caseof active ingredients that must be headed to the gut withoutdegradation, a protection against stomach acidity is needed. Coatingssuch as enteric coatings have been used to solve this problem.

Conventionally, the oral route cannot be used for the delivery ofmacromolecular drugs such as proteins and peptides owing to limitedtransport across the epithelial membrane. This challenge can potentiallybe overcome through the use of chemical permeation enhancers, whichaffect transcellular and/or paracellular transport routes.

Dohan and Vervelle (FR 2932385; WO2009153419) describe a compositioncomprising original natural extracts (from vegetable or animal origin)for oral or skin application for humans or animals, characterised inthat said natural extracts are microencapsulated using a spherulitetechnique, and in that the application is done via a gel, toothpaste,stick or mouthwash on the oral tissues (particularly on gums, cheekmucosa, and back of the tongue), or via a gel, a cream or a stick onexternal tissues (skin, mucosa).

Nelson and Allred (US20090155392) describe methods and systems for thesublingual and buccal administration of herbal supplements, and moreparticularly, to the sublingual and buccal administration of Guaraná,which allows for considerably reducing the therapeutic dose, with theadditional advantage of increasing the quickness of the beneficialeffects.

Borowy-Borowski (US20080160077) describes a formulation methodology forbioactive lipophilic molecules, such as Coenzyme Q10 and its reducedanalogs (ubiquinols). Further provided are methods of producing soft gelcapsules of this formulation.

Bell et al. (CA2293365) describes improved confectionery compositionswhich have a substantial reduction in the unpleasant organolepticsensations associated with the release of functional ingredients fromthe confection in the oral cavity.

It would be highly desirable to be provided with a novel oral deliveryvehicle for administration of active molecules to a subject whichby-pass the gastro-intestinal tract.

It is an object of the present disclosure to provide a novel oraldelivery for administration of active molecules to a subject whichby-passes the gastro-intestinal tract.

According to an embodiment, there is provided a buccal delivery dosageform for oral mucosal absorption of an active ingredient in the mouth ofa subject wherein said buccal delivery dosage form comprises:

a) at least one chemical permeation enhancer to maximize uptake ofactive ingredient from mouth tissues;

b) at least one excipient for suspending the active ingredient;

c) at least one texture modulator to increase retention time of saiddosage form in the mouth to maximize uptake of the active ingredient;and

d) at least one pH modulator to decrease or buffer the oral pH of thedosage form during mastication to maximize enzymatic degradation of thedosage form in the mouth.

According to an embodiment, there is provided a buccal delivery dosageform for administration of an active ingredient in the mouth of asubject with a by-pass of gastrointestinal tract metabolism; which maycomprise at least one of the following ingredients:

-   -   a) a chemical permeation enhancer to maximize uptake of active        ingredient from mouth tissues;    -   b) an excipient comprising a pharmaceutically inert substance        for suspending the active ingredient;    -   c) a texture modulator to increase retention time of said dosage        form in the mouth to maximize uptake of the active ingredient.

Features and advantages of the subject matter hereof will become moreapparent in light of the following detailed description of selectedembodiments, as illustrated in the accompanying figures. As will berealized, the subject matter disclosed and claimed is capable ofmodifications in various respects, all without departing from the scopeof the claims. Accordingly, the drawings and the description are to beregarded as illustrative in nature, and not as restrictive and the fullscope of the subject matter is set forth in the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages of the present disclosure will becomeapparent from the following detailed description, taken in combinationwith the appended drawings, in which:

FIG. 1: Functional Khlôros Micros-spheres according to the presentinvention of 3.5 mm in diameter and 35 mg each (0.9% of Riboflavine)

FIG. 2: Functional Khlôros Gel according to the present invention madewith riboflavine powder 0.9%.

FIG. 3: Liberation of Riboflavin (0.9%) as a function of time. Passiveliberation (square) and active liberation (mastication) (lozenge).

FIG. 4: Liberation of riboflavin from a gel (0.9% riboflavin) preparedwith riboflavin powder (lozenge) and with Khlôros microspheres accordingto the present invention (square).

FIG. 5: Liberation of actives from functional Khlôros gel according tothe present invention (9% of Hibiscus subdariffa granulated flowerpowder) as a function of artificial mastication method. The active isdetected by absorbance at 518 nm. Control, no artificial mastication(dot), medium compression and soft shearing (line) and mediumcompression and hard shearing (black).

FIG. 6: Mouth absorption of active. Photospectroscopic detection ofactive(s) from Hibiscus subdariffa at 518 nm. Percentage of active mouthabsorption calculated in function of the control (no mouth passage). Themouth absorption is compare the mastication process (black) and withoutmastication (vertical lines) with three mouth incubation/masticationtime (30, 60 and 90 seconds).

FIG. 7a : Variation of pH in function of the granulometry of theSugar-CO₂. The concentration of the Sugar-CO₂ is 10% (w/v). The pHvariation is calculated by the subtraction of the pH at the beginningand the pH after complete solubilisation of the Sugar-CO₂.

FIG. 7b : Variation of the pH in function of the concentration of theSugar-CO₂ Granulometry of the Sugar-CO₂ is 1.35 mm.

FIG. 8: Liberation of active(s) at 518 nm from Hibiscus subdariffa chew,in function of time.

FIG. 9: Liberation of active(s) from Hibiscus subdariffa at 518 nm infunction of the granulometry of the chew (0.7 mm; 0.93 mm; 1.35 mm; 2.0mm).

FIG. 10: Comparison of the water and saliva liberation of active(yohimbine) in chew. The chew was masticated 2 minutes.

It will be noted that throughout the appended drawings, like featuresare identified by like reference numerals.

In embodiments there is disclosed a novel way to promote the absorptionof active ingredients using three routes comprised in the mouth: buccal,sublingual, and local routes, which are all active during a masticationprocess. One faces a challenge in the case of active ingredient thathave to be delivered for systemic absorption without degradation or witha controlled dispersion. The drug transport mechanism through the buccalmucosa involves two principal routes: the transcellular (intracellular)and paracellular (intercellular) pathways. The transcellular routeinvolves the crossing of the cellular membranes with a polar and a lipiddomain, whereas the paracellular route essentially implicates thepassive diffusion through the extracellular lipid domain. Ionic drugsusually diffuse through the intercellular space, whereas hydrophobicdrugs are able to pass through the cellular membranes.

The buccal drug delivery system has been accepted as a potentialnon-invasive route of drug administration, with the advantages ofavoiding the first-pass metabolism, sustained therapeutic action andbetter patient compliance. The oral cavity is an attractive site for thedelivery of drugs. The oral cavity includes the floor of the sublingualmucosa (mouth), palatal mucosa, buccal mucosa (the inside of the cheeks)and the gingival mucosa (gums). There are considerable differences inpermeability between different regions of the oral cavity because of thediverse structures and functions of the different oral mucosa. Ingeneral, the permeability of the oral mucosa is greatest for thesublingual and lowest for the palatal mucosa, with the buccal mucosahaving intermediate permeability. The buccal and sublingual sectors arethe most appropriate for drug delivery as it is possible to realizelocal effect (mucosal) and systemic effect (transmucosal) of drugadministration. The buccal drug delivery system also provides manyadvantages, such as avoiding hepatic first-pass metabolism, nopresystemic metabolism, ease of administration, fast onset of action ofthe active ingredient(s), and unlike the skin, it has a rapid cellrecovery, hence it is used for local as well as for systemic effect.

According to one embodiment of the present invention, the dosage form ofthe present invention may comprise permeation enhancers.

Chemical Permeation enhancers. Membrane permeability is the limitingfeature for many drugs in the progress of the buccal delivery approach.The epithelium that lines the buccal mucosa is a very effective obstacleto the permeation and hence absorption of drugs. To mitigate thisbarrier and to facilitate the permeation through buccal mucosa,permeation enhancers are used.

According to one embodiment of the present invention, chemicalpermeation enhancers work through many mechanisms. They may act bychanging mucus rheology, that is, by reducing the viscosity of themucus. Mucus forms a viscoelastic layer of varying thickness thataffects drug absorption. Most chemical permeation enhancers act bydisturbing the intracellular lipid packing by interaction with eitherlipid packing or protein components, thus increasing the fluidity of thelipid bilayer membrane. Fluidization of the plasma membrane, looseningof the tight junctions between cells, and inhibition of proteases are afew of the mechanisms.

The chemical permeation enhancer may be chosen from the chelators,surfactants, fatty acids and derivatives thereof, terpenes,cyclodextrins, azone, chitosan, and lysalbinic acid.

There are various chemical permeation enhancers, such as:

Chelators: for example EDTA, EGTA, citric acid, salicylates, N-acylderivatives of collagen, and enamines (N-amino acyl-derivatives of3-diketones).

Surfactants: such as sodium lauryl sulfate,polyoxyethylene-9-laurylether, and polyoxyethylene-20-cetylether; andnatural surfactant such as bile salts (sodium deoxycholate, sodiumglycocholate, and sodium taurocholate).

Fatty acids and their derivatives: such as sodium caprylate, sodiumcaprate, sodium laurate, lauric acid, oleic acid, lecithin,phospholipids >60% (phosphatidylcholine, phosphatidylethanolamine,phosphatidylinositol, phosphatidic acid) monoolein and acylcarnitines,have been shown to reduce the thickness of the unstirred water layeradjacent to the mucosal membrane, and by disrupting intercellular lipidpacking.

Terpenes: is a very safe and effective class of chemical permeationenhancers obtained from natural sources (example: I-menthol).

Cyclodextrins: cyclic oligosaccharides, are also recognized as anenhancer of the buccal permeation.

Azone: acts by creating a region of fluidity in intercellular lipids,and alcohols work by reorganizing the lipid domains and by changingprotein conformation.

Chitosan and its derivates have been used to enhance the permeation ofmedicaments by means of the buccal route and have been found to be apotential penetration enhancer for transmucosal (intestinal, nasal,buccal and vaginal) absorption of drugs.

Lysalbinic acid was found to be a new absorption enhancer for the buccaldelivery of peptide drugs.

The terms “texture and temperature modulator” or “texture modulator” areintended to mean different ingredients are used to modify the meltingpoint (MP) temperature of a mixture, including for example, withoutlimitations Menthol crystals, Stearic acid, Candelilla wax, Carnaubawax, and other waxes, butters and oils.

The buccal delivery dosage form may further comprise a temperaturemodulator to modulate temperature of the dosage form to maximizeenzymatic degradation in the mouth.

Texture and temperature modulators. Different ingredients are used astexture modulators to modify the melting point (MP) temperature of amixture. Menthol crystals (MP≈42° C.), Stearic acid (MP≈65.5° C.),Candelilla wax (MP≈67° C.), Carnauba wax (MP≈83° C.), other ingredientsmay be used among others, such as wax, butter and oil.

The texture of food leads to a certain sequence of chewing whichcontinually modifies the mastication process. During the masticationprocess, the texture of food is dependent of the chewing sequence (i.e.mechanical influence related to the food grinding), the fluctuation ofpH, the presence of saliva and the appearance of salivary enzyme, whichall happen in the oral cavity in a coordinated manner to helpdegradation. The texture of food throughout the mastication process isalso governed by the hardness and the size of the product as well as itselasticity, plasticity, stickiness, and brittleness among others.Feldman and Cryer (1999) have demonstrated in human that chewabletablets of aspirin are absorbed quicker than solid tablets. Moreover,they showed that chewable tablets were more effective at decreasingserum thromboxane B2 (acting in the cascade of clot formation). Also, ithas been demonstrated that chewing on a raw carrot for a longer periodof time allows more β-carotene to be liberated.

In one aspect, the excipient may be a hydrocolloid.

The hydrocolloid may be selected chosen from agar, agarose, alginates,base gum, carrageenan (iota, kappa, lambda), cellulosics, chicle,chitosan, gelatin, gellan gum, guar gum, gum arabic, locust bean gum,pectin, soybean gel, starch, whey protein, xanthan gum, and derivativesthereof.

Colloids: A colloid is a substance microscopically dispersed evenlythroughout another substance. A colloidal system consists of twoseparate phases: a dispersed phase and a continuous phase. Ahydrocolloid is defined as a colloidal system, in which the colloidparticles are dispersed in water. A hydrocolloid has colloid particlesspread throughout the water and depending on the quantity of wateravailable, that system can be a gel or a solid (liquid). Hydrocolloidsused in food are often polysaccharides of high molecular weight,extracted for example from plants and seaweeds or produced by microbialsynthesis. The raw plant materials are then further processed, e.g. bythe addition of functional side-groups, by hydrolysis and/orpurification to obtain a standardized product to ensure a qualitystandard.

There are several hydrocolloids in food product. These include, withoutlimitation, agar, agarose, alginates, carrageenan (iota, kappa, lambda),cellulosics, chicle, chitosan, gelatin, gellan gum, guar gum, gumarabic, gum base, locust bean gum, pectin, soybean gel, starch, wheyprotein, xanthan gum, derivatives thereof and combinations thereof.

In one aspect, the excipient is a gum base which comprises polyols (e.g.gum base with isomalt, gum base with sorbitol).

pH modulators: Antacids increased oesophageal pH independent of gastricpH, demonstrating that chewing antacids controls oesophageal aciditymore effectively than swallowing antacid tablets.

Bicarbonate is often referred to as the major buffer of saliva. Althoughbicarbonate in solution can act as a pH buffer, in an open system suchas the mouth, bicarbonate acts mainly to neutralize acid (H⁺):

HCO₃ ⁻+H⁺

H₂CO₃

=CO₂+H₂O

In the mouth the concentration of carbonic acid stays constant at about1.3 mMol/L. The pH and the bicarbonate concentration do however change.Both the pH and the bicarbonate concentration are very important andcentral to how saliva protects teeth. Saliva is unique in that itcontains a form of carbonic anhydrase called Carbonic Anhydrase VI whichis secreted by serous acinar cells of the parotid and submandibularglands. No other secreted fluid contains such an enzyme. Carbonicanhydrase drives the reaction converting carbonic acid to carbon dioxideand water (see above) which effectively collects available protons.Recent work has shown that this carbonic anhydrase forms part of thetooth pellicle where it is available to convert any protons produced byoverlying dental plaque to carbon dioxide and water so long asbicarbonate is available.

The concentration of bicarbonate (NaHCO₃ and bicarbonate ion HCO₃ ⁻) insaliva is linked to the flow rate. As the rate of saliva productionincreases, more bicarbonate ion is produced as a by-product of cellmetabolism. Stimulated saliva contains more bicarbonate than restingsaliva. This is convenient since during eating when saliva flow isincreased, plaque acid is produced in higher quantities. This ensuresthat there is enough bicarbonate present to capture surplus protons. Thedissociation of carbonic acid into bicarbonate and a proton is animportant reaction (The pK of this reaction is 6.1; pH=pK+log [HCO₃⁻]/[H₂CO₃]).

As mentioned above, the carbonic acid concentration of saliva isconstant at about 1.3 mMol/L but the bicarbonate concentration varieswith the flow rate (during mastication). This is possible because ofbicarbonate pumps situated in the secretory units of salivary glands.For example, 3 values of bicarbonate concentration were considered inrelation with flow rate:

Low saliva flow→2 mMol/L pH=6.29

Intermediate saliva flow→30 mMol/L pH=7.46

High saliva flow→60 mMol/L pH=7.76

During mastication, the addition of CO₂ (e.g. to create an effervescencesensation in the mouth) helps to regulate the optimum pH in the mouth.Adding CO₂ also promotes the absorption of molecules though the oralcavity. Adding CO₂ in the chewable vehicle is also a great indicator ofthe liberation of active ingredient. Effervescence may also be obtainedby the use of an acid, for example citric acid, and a carbonate.According to one embodiment of the present invention, an entrapped-CO₂is used. As used herein “entrapped-CO₂” refers to CO₂ that is entrappedin a suitable agent. For example, the CO₂ can be entrapped in suitablefood product such as sugars, salts used in food products or othersuitable agents. According to one embodiment of the present invention,the entrapped-CO₂ may be used alone. According to another embodiment ofthe present invention, the entrapped-CO₂ may be used in combination withan acid and a carbonate. In one aspect, the entrapped-CO₂ is CO₂entrapped in sugar (CO₂-sugar). According to one embodiment of thepresent invention, the CO₂-sugar may be used alone. According to anotherembodiment of the present invention, the CO₂-sugar may be used incombination with an acid and a carbonate. The acid and the carbonate maybe also used alone. Preferably, the CO₂-sugar is used, alone or incombination with an acid and carbonate. Most preferably, the CO₂-sugaris used alone. CO₂-sugar is preferably used to obtain the pH regulatingeffect described above.

According to one embodiment of the present invention, the CO₂-sugar,also known as popping sugar, comes in the shape of small bits of meltedsugars (such as sucrose, lactose and glucose syrup) within which carbondioxide has been introduced. According to the present invention, it ismade by mixing ingredients including sugars, including for examplewithout limitations lactose (milk sugar), corn syrup, glucose syrup,etc, or combinations thereof, and heating until they melt into dust,then exposing the mixture to pressurized carbon dioxide gas (about 600pounds per square inch; or approx. 41.37 Bar) and allowing the sugar/gasmixture to cool, thereby entrapping CO₂ gas therein. The process causestiny high pressure bubbles to be trapped inside the sugar. According toone embodiment of the present invention, the CO₂-sugar is preparedwithout any additional ingredient. According to another embodiment ofthe present invention, the CO₂-sugar may also be prepared from a sugarcomposition to which one or more ingredients have been added. Accordingto one embodiment, the ingredient may be one or more of the activeingredients according to the present invention.

In one aspect, the pH modulator can be used to keep the pH in the mouthof the subject at the desired pH for release of the active from thedosage form and for oral mucosal absorption. As shown in examples XV andXIV, using different concentrations and granulometry of Sugar-CO₂ theinventor has found that under certain conditions the pH variationsfollows a logarithmic curve. Interestingly, one can extrapolate thatentrapped-CO₂ can allow for a delivery of active in a subject that canbe adapted based on the mastication pattern of the subject.

The mastication activity stimulates the production of saliva includingthe liberation of enzyme activities and favors the breaking down of thegranules and the liberation of an active ingredient(s) extract in themouth.

The fast liberation of the actives, permit their absorption by the oralcavity mucosa, through the trans- and/or paracellular routes.

The addition of CO₂ regulates the pH and improves the salivaconstituents, such as enzymes, for a more efficient absorption andcontributes to preserving or enhancing the activity of amylase, whichwill increase the rate of starch viscosity thinning.

The buccal delivery dosage form may further comprise a sensory indicatorof active ingredient release from the dosage form. The indicator may beCO₂.

In one aspect, after mixing of the mixture and compression intogranules, the effervescence effect is still present.

Up to 70% of the total mucin found in saliva is contributed by the minorsalivary glands. At physiological pH the mucus network carries anegative charge (due to the sialic acid and sulfate residues) which mayplay a role in mucoadhesion. At this pH mucus can form a stronglycohesive gel structure that will bind to the epithelial cell surface asa gelatinous layer (Gandhi, R. E. and Robinson, J. R., Bioadhesion indrug delivery, Ind. J. Pharm. Sci., 50:145-152, 1988). The salivary pHranges from 5.5 to 7 depending on the flow rate. At high flow rates, thesodium and bicarbonate concentrations increase leading to an increase inthe pH.

Without being bound to a specific theory, the present inventors believethat to maximize mucosal absorption, the formulation matrix of thepresent invention can change the ionicity and polarity of the cellularmucosa domains.

As shown in Example XIII and on FIG. 9, the size of the particles can beused to modify the liberation of active ingredients from the dosageform. In one aspect, the biggest particle size used when preparing thedosage form of the invention is between about 0.1 mm to about 3 mm. In afurther aspect, the biggest particle size used in the dosage form of theinvention is preferably between about 0.5 mm to about 2 mm; morepreferably between about 0.5 mm to about 2 mm and most preferablybetween 0.7 mm to about 1 mm. The particle size is the size of theparticles prior to compression into the desired dosage form. Theparticle size is measured by known methods (e.g. with sieves).

According to some embodiments, the preparation process and the selectionof the ingredients of the vehicle of the present invention will allow toobtain the adequate or desired elasticity, porosity and resistance toshearing. Methods for the preparation of oral dosage forms are wellknown in the art. See for example Handbook of Pharmaceutical Excipients,Sixth edition 2009. Edited by R C Rowe, P J Sheskey and M E Quinn, orRemington: The Science & Practice of Pharmacy 21^(th) Edition,Lippincott Williams and Wilkins, Philadelphia, Pa. (2005).

In one aspect, the buccal delivery dosage form as defined herein is abuccal delivery dosage form wherein the delivery of active ingredient inthe mouth of the subject is adaptable based on the mastication patternof said subject.

According to one embodiment of the present invention, micro-tablets maycontain active ingredient (up to about 80%), cellulose or other agents,such as for example, without limitations lactose monohydrate 315, orlactose monohydrate 316, or powdered mannitol, CO₂-sugar (up to 30%),chemical permeation enhancers (lauric acid in coco oil or other chemicalpermeation enhancers as mentioned above, texture and temperaturemodulators (Candelilla wax or other, as mentioned above).

In one aspect, the dosage form of the invention have Matrix CohesiveForce (MCF) between 2 and 5. The MCF is the force of intermolecularattraction between the particles of the amalgam matrix. These forces aregoverned by the nature of the molecules, the compressive force, particlesize and the temperature of the ingredients. The MCF is determined usingan apparatus or by qualitative observation. The MCF is a factor of thetexture, the cohesion and the consistency of the matrix duringmastication. Typically, a high MCF is characterized by a weak cohesionbetween the particles and is usually indicative of a fast release. A lowMCF is characterized by a strong cohesion between the particles and isusually indicative of a slower release. For a chewable dosage form, itis preferable that the matrix keeps its integrity in order to maximizethe liberation and buccal mucosa absorption of the actives. In oneaspect of the present invention, the MCF should be between 2 to 5 tomaximize and control the liberation and buccal mucosa absorption ofactives. The following table summarizes MCF and the relevant evaluationcriteria.

Matrix Cohesive Force (MCF) Evaluation criteria 1 Very hard matrix -very strong cohesion particle (time stable) 2 Hard matrix - strongcohesion particle (time stable) 3 Medium to soft matrix - Strongcohesion particle (time stable) 4 Medium to soft matrix - Mediumcohesion particle (time stable) 5 Medium to soft matrix - Weak cohesionparticle (time stable) 6 Medium to soft matrix - Weak cohesion particle(time not-stable)

Unless indicated otherwise weight percentages are indicated by weight ofthe total composition of the dosage form.

According to one embodiment, the chemical permeation enhancer and thetexture modulator are mixed to prepare a modulatory mixture comprisingpermeation enhancers as well as texture modulators. The permeationenhancer may be employed in a ratio of about 100% to 0% texturemodulator, or from about 99% permeation enhancer to about 1% texturemodulator, or from about 98% permeation enhancer to about 2% texturemodulator, or from about 97% permeation enhancer to about 3% texturemodulator, or from about 96% permeation enhancer to about 4% texturemodulator, or from about 95% permeation enhancer to about 5% texturemodulator, or from about 94% permeation enhancer to about 6% texturemodulator, or from about 93% permeation enhancer to about 7% texturemodulator, or from about 92% permeation enhancer to about 8% texturemodulator, or from about 91% permeation enhancer to about 9% texturemodulator, or about 90% permeation enhancer and about 10% texturemodulator. Preferably, the ratio may be about 95:5.

According to one embodiment, the buccal delivery dosage comprises fromabout 0.5% w/w to about 15% w/w, preferably from about 1% w/w to about5% w/w or more preferably from about 3% w/w to about 4% w/w of the atleast one chemical permeation enhancer.

According to one embodiment, the buccal delivery dosage comprises fromabout 20% w/w to about 90% w/w, preferably from about 50% w/w to about85% w/w, or more preferably from about 70% w/w to about 85% w/w of theat least one excipient. In one aspect, if the excipient is a gum basewith polyols, the delivery dosage will preferably comprise from about50% w/w to about 90% w/w and more preferably from about 70% w/w to about90% w/w. In one aspect, if the excipient is a gum base without polyols,the delivery dosage will preferably comprise from about 20% w/w to about60% w/w.

According to one embodiment, the buccal delivery dosage comprises fromabout 0.1% w/w to about 6% w/w, preferably from about 0.5% w/w to about5% w/w, more preferably from about 0.5% w/w to about 1% w/w or mostpreferably about 1% w/w of the at least one texture modulator.

According to one embodiment, the buccal delivery dosage form comprisesfrom about 0.5% w/w to about 30% w/w, preferably from about 1% w/w toabout 20% w/w, more preferably from about 2% w/w to about 15% w/w ormost preferably about 5% w/w of the at least one pH modulator.

The buccal delivery dosage form may be chewable.

In one aspect, the active ingredient of the buccal delivery dosage asdefined herein is dispersed in the mouth of the subject by mastication.

In one aspect, the active ingredient of the buccal delivery dosage asdefined herein may be coated. The coating may be functional oraesthetic. In one aspect, the coating can be used to improve shelfstability (e.g. by protecting the ingredients degradation (e.g. viaoxidation or light exposure). In one aspect, the coating may be a sugarcoating or a film coating. In a further aspect, the coating may includean active ingredient as defined herein.

The expression “buccal delivery dosage form” is intended to mean avehicle or carrier for administration of an active in the mouth of asubject with a by-pass of gastrointestinal tract metabolism. Such dosageforms include pill, tablet, gum, micro-tablet, micro-spheres (e.g. withdiameters of about 1 μm to about 1 mm), nano-spheres (e.g. withdiameters of about 100 nm, microsomes (about 1 μm to about 1 mm), gel,colloid, colloidosome, nano-capsule (e.g. with diameters of about 1 μm),pastille, paste, syrup, micronized powder, crystals, liquid, aerosol,caplet thin film or capsule.

In one aspect, the buccal delivery dosage form of the present inventionsubstantially avoids the first-pass metabolism. Unless indicatedotherwise, first-pass metabolism is defined as a pathway in which theactive ingredients are modified, activated, or inactivated before theyenter the systemic circulation, or are left unchanged and excreted.

The term “subject” is intended to mean any mammals, including withoutlimitation, human, equine, bovine, caprine, feline, canine, ovine,rodents, etc.

Active Ingredients

The buccal delivery dosage form may further comprise an activeingredient. The active ingredient may be a plant extract, a naturalcompound or a pharmaceutical drug. It is understood that the activeingredient may have a known biological effect.

The term “active ingredient” is intended to mean any pharmaceutically,pharmacologically, or biologically active substance such as apharmaceutical drug, or a vitamin that is biologically active. Theseinclude without limitations enzyme inhibitors (e.g. carbonic anhydraseinhibitors), ion channel blockers (e.g. calcium channel blockers),antacids, amino acid, reflux suppressant, antiflatulents,antidopaminergics, proton pump inhibitors, H₂-receptor antagonists,cytoprotectants, prostaglandin and prostaglandin analogues, laxatives,antispasmodics, antidiarrheals, bile acid sequestrants, opioids,beta-receptor blocker, diuretics, cardiac glycosides, antiarrhythmics,nitrate, antiangials, vasoconstrictor, vasodilators, peripheralactivators, ACE inhibitors, angiotensin receptor blockers,alpha-blocker, anticoagulants, heparin, antiplatelet drugsfibrinolytics, anti-hemophilic factors, haemostatic drugs,hypolipidaemic agents, statins, hyphotics, anaesthetics, antipsychotics,antidepressants (such as tricyclic antidepressant, monoamine oxidase Binhibitors, lithium salts and selective serotonin reuptake inhibitors),antiemetics, anticonvulsants/antiepileptics, anxiolytics, barbiturates,folic acid, phenolic compounds, movement disorder drugs, fatty acids(such as oleic acid, linoleic acid, Myristoleic acid, Palmitoleic acid,Sapienic acid, α-Linolenic acid or omega-3, Arachidonic acid,Eicosapentaenoic acid, Erucic acid, Docosahexaenoic acid, Lauric acid,Myristic acid, Palmitic acid, Stearic acid, Arachidic acid, stimulants,benzodiazepine, cyclopyrrolones, dopamine agonists/antagonists,antihistamines, bromide, scopolamine, cholinergics, anticholinergics,emetics, cannabinoids, 5-HT antagonists, NSAIDs (such as COX-2 selectiveinhibitors), opioids, orphans drugs (such as paracetamol), musclerelaxant, neuromuscular drugs, anticholinesterases, adrenergic blockers,antibiotics, aminoglycosides, sulfa drugs, fluoroquinolones, antiviraldrugs, anti-fungal, corticosteroids, mast cell inhibitors, prostaglandinagonists/inhibitors, steroids, antiseptics, anesthetics, androgens,antiandrogens, gonadotropin, human growth factor, insulin,antidiabetics, thyroid hormones, antityroid drugs, calcitonin,diphosponate, vasopressin analogues, quinolones, 5-alpha reductaseinhibitor, selective alpha-blockers, sildenafils, tadalafils, fertilitydrugs, hormonal contraception, ormeloxifene, antifibrinolytics, folliclestimulating hormone, luteinising hormone, gamolenic acid, gonadotropinrelease inhibitor, progestin, oestrogen, gonadorelin, clomiphene,tamoxifen, diethyl stilbestrol, antileprotics, antituberculous drugs,antimalarials, anthelmintics, amoebicides, antivirals, antiprotozoals,vaccines, immunoglobulins, immunosuppressants, interferons, monoclonalantibodies, anti-allergics, cytotoxic drugs, therapeutic antibodies,somatostatin inhibitors, recombinant interleukins, G-CSF,erythropoietin, vitamins, pigments, antioxidant, laxative, mineralsupplements (such as calcium, chromium, folate, iron, magnesium,selenium, nitrate . . . ), natural compounds, including withoutlimitations Bilobalide, Ginkgolide, hypericine, Hyperforin, Silymarine,Silibinin, a Lignan, Diosgenine, curcumin, hydroxycitric acid,eleutherocide B, eleutherocide E, a phytosterol, a saponin, sarsapicacid, yohimbine, gingerol, phytosterols including without limitationsdiosgenine, brassicasterol, campaestrol, 5α-cholestane, β-sitosterone,β-sitosterol, stigmasterol, etc.

The plant extract may be chosen from Absinthe (Artemisia absinthum),Alfalfa (Medicago sativa), Aloe (Aloe barbadensis), Angelica (Angelicaarchangelica and sinensis), Anise (Pimpinella anisum), Arnica (Arnicamontana), Ashwaganda (Withania somnifera), Astragalus (Astragalusmembranaceus), Betony (Stachys/Betonica officinalis),Bilberry/Huckleberry (Vaccinium spp.), Bitter melon fruit (Momordicacharantia), Black cohash (Cimicifuga racemosa), Bladderwrack (Fucusversiculosus), Blessed thistle (Cnicus benedictus), Blue cohosh(Caulophyllum thalictroides), Boneset (Eupatorium perforatum), Burdock(Arctium lappa), Caesalpinia benthamiana, Calendula (Calendulaofficinalis), California poppy (Eschscholzia californica), Caraway(Carum carvi), Cardamom (Elettaria cardamomum), Cascara (Rhamnuspurshiana), Catnip (Nepeta cataria), Cayenne (Capsicum frutescens),Cedar, Western (Thuja plicata or occidentalis), Chamomile (Matricariarecutita), Chaparral (Larrea mexicana), Chaste tree berry (Vitex agnuscastus), Chickweed (Stellaria media), Cinnamon (Cinnamomum spp.),Cleavers (Galium aparine), Coltsfoot (Tussilago farfara), Comfrey(Symphytum officinalis), Corn silk (Zea mays), Corynanthe yohimbe, Crampbark (Viburnum opulus), Dandelion (Taraxacum officinalis), Devil's club(Oplopanax horridus), Dioscorea villosa, Dong quai (Angelica sinensis),Echinacea (Echinacea spp.), Elder flowers (Sambucus spp.), Elecampane(Inula helenium), Eyebright (Euphrasia officinalis), Fadogia agrestis,Fennel (Foeniculum vulgare), Fenugreek (Trigonella foenum-graecum),Feverfew (Tanacetum parthenium), Flax seed (Linum usitatissimum),Garcinia Cambogia, Garlic (Allium sativa), Geranium (Geraniummaculatum), Ginger (Zingiber officinalis), Ginkgo (Ginkgo biloba),Ginseng (Panax spp.), Goldenrod (Solidago spp.), Goldenseal (Hydrastiscanadensis), Gotu kola (Centella asiatica), Gravel root (Eupatoriumpurpureum), Hawthorne (Crataegus spp.), Hibiscus subdariffa, Hops(Humulus lupulus), Horehound (Marrubium vulgaris), Horsetail (Equisetumarvense), Hippophae rhamnoides, Hyssop (Hyssopus officinalis), Kava kava(Piper methysticum), Lady's mantle (Alchemilla vulgaris), Lemon balm(Melissa officinalis), Lepidium meyenii, Licorice (Glycyrrhiza glabra),Linden flower (Tilia spp.), Lobelia (Lobelia inflata), Lomatium(Lomatium dissectum), Lungwort (Sticta pulmonaria), Marshmallow (Altheaofficinalis), Massularia acuminate, Meadowsweet (Filipendula ulmaria),Microdesmis keayana, Milk thistle (Silybum marianum), Morindacitrifolia, Motherwort (Leonurus cardiaca), Mucuna pruriens, Mugwort(Artemisia vulgaris), Mullein (Verbascum thapsus), Myrrh gum (Commiphoramyrrha), Nettle (Urtica spp.), Noni (Morinda citrifolia), Nopal (Opuntiaficus indica), Oat (Avena sativa), Oenothera biennis, Old man's beard,Usnea (Usnea spp.), Oregon grape root and barberry (Mahonia spp.), Osha(Ligusticum porteri), Parsley (Petroselinum crispum), Passionflower(Passiflora incarnata), Peppermint (Mentha piperita), Plantain (Plantagospp.), Poplar buds (Populus spp.), Red clover (Trifolium pratense), Redraspberry (Rubus idaeus), Red root (Ceanothus americanus), RhodiolaRosea, Rosemary (Rosmarinus officinalis), Sage (Salvia officinalis),Saint John's wort (Hypericum perforatum), Saw palmetto (Serenoa repens),Sea-buckthorn (Hippophae rhamnoides), Sesame seed (Sesamum indicum),Siberian ginseng (Eleutherococcus senticosus), Skullcap (Scutellarialaterifolia), Slippery elm (Ulmus spp. (rubra, fulva)), Thyme (Thymusvulgaris), Triblus terrestris, Tumeric (Curcuma longa), Thuyaoccidentalis, Uva ursi (Arctostaphylos uva ursi), Valerian (Valerianaofficinalis), Vervain (Verbena officinalis), White oak bark (Quercusalba), Wild cherry (Prunus spp.), Willow (Salix spp.), Yarrow (Achilleamillefolium), Yellow dock (Rumex crispus/obtusifolius), or combinationsthereof.

The active ingredient may also be specific natural compounds, includingwithout limitations Astaxanthin, Bilobalide, Biotine, Catechine,Choline, Coenzyme Q₁₀, Conjugated, Curcumine, Lecithin, linoleic acid,Ginkgolide, Glucosamine, Hypericine, Hyperforin, Silymarine, Silibinin,a Lignan, Diosgenine, hydroxycitric acid, eleutherocide B, EleutherocideE, L-carnitine, Leucine, Megastigmane glycoside, Melatonine,Niacinamide, Niacine, Omega-3, Pantothenic acid, a phytosterol,Phospholipids, Pinolenic acid, Resveratrol, Riboflavine, Rosiglitazone,Serotonin, Theobromine, Theophylline, Thiamine, g-aminobutyric acid(pathway), a saponin, sarsapic acid, Vitamin B₁₂, Yohimbine, gingerol,or combinations thereof.

The phytosterol may be chosen from diosgenine, brassicasterol,campaestrol, 5α-cholestane, β-sitosterone, β-sitosterol, stigmasterol,or combinations thereof.

The active ingredient may be chosen from Colostrum (Shing et al, J.Appl. Physiol. 2007. Effects of bovine colostrum supplementation onimmune variables in highly trained cyclists. 102, 1113-1122).

According to some embodiments of the present invention, the activeingredients are plant extracts. Preferably, the plant extracts includewithout limitations. Preferably, the plant extracts include withoutlimitations Absinthe (Artemisia absinthum), Acai, Alfalfa (Medicagosativa), Aloe (Aloe barbadensis), Angelica (Angelica archangelica andsinensis), Anise (Pimpinella anisum), Arnica (Arnica montana),Ashwaganda (Withania somnifera), Astragalus (Astragalus membranaceus),Betony (Stachys/Betonica officinalis), Bilberry/Huckleberry (Vacciniumspp.), Bitter melon fruit (Momordica charantia), Black cohash(Cimicifuga racemosa), Bladderwrack (Fucus versiculosus), Blessedthistle (Cnicus benedictus), Blue cohosh (Caulophyllum thalictroides),Boneset (Eupatorium perforatum), Burdock (Arctium lappa), Caesalpiniabenthamiana, Calendula (Calendula officinalis), California poppy(Eschscholzia californica), Caralluma fibriata, Caraway (Carum carvi),Cardamom (Elettaria cardamomum), Cascara (Rhamnus purshiana), Catnip(Nepeta cataria), Cayenne (Capsicum frutescens), Cedar, Western (Thujaplicata or occidentalis), Chamomile (Matricaria recutita), Chaparral(Larrea mexicana), Chaste tree berry (Vitex agnus castus), Chickweed(Stellaria media), Cinnamon (Cinnamomum spp.), Cleavers (Galiumaparine), Coltsfoot (Tussilago farfara), Comfrey (Symphytumofficinalis), Corn silk (Zea mays), Corynanthe yohimbe, Cramp bark(Viburnum opulus), Curcuma, Dandelion (Taraxacum officinalis), Devil'sclub (Oplopanax horridus), Dioscorea villosa, Dong quai (Angelicasinensis), Echinacea (Echinacea spp.), Elder flowers (Sambucus spp.),Elecampane (Inula helenium), Eyebright (Euphrasia officinalis), Fadogiaagrestis, Fennel (Foeniculum vulgare), Fenugreek (Trigonellafoenum-graecum), Feverfew (Tanacetum parthenium), Flax seed (Linumusitatissimum), Garcinia Cambogia, Garlic (Allium sativa), Geranium(Geranium maculatum), Ginger (Zingiber officinalis), Ginkgo (Ginkgobiloba), Ginseng (Panax spp.), Goldenrod (Solidago spp.), Goldenseal(Hydrastis canadensis), Gotu kola (Centella asiatica), Gravel root(Eupatorium purpureum), Hawthorne (Crataegus spp.), Hibiscus subdariffa,Hops (Humulus lupulus), Horehound (Marrubium vulgaris), Horsetail(Equisetum arvense), Hippophae rhamnoides, Hyssop (Hyssopusofficinalis), Kava kava (Piper methysticum), Lady's mantle (Alchemillavulgaris), Lemon balm (Melissa officinalis), Lepidium meyenii, Licorice(Glycyrrhiza glabra), Linden flower (Tilia spp.), Lobelia (Lobeliainflata), Lomatium (Lomatium dissectum), Lungwort (Sticta pulmonaria),Marshmallow (Althea officinalis), Massularia acuminate, Meadowsweet(Filipendula ulmaria), Microdesmis keayana, Milk thistle (Silybummarianum), Morinda citrifolia, Motherwort (Leonurus cardiaca), Mucunapruriens, Mugwort (Artemisia vulgaris), Mullein (Verbascum thapsus),Myrrh gum (Commiphora myrrha), Nettle (Urtica spp.), Noni (Morindacitrifolia), Nopal (Opuntia ficus indica), Oat (Avena sativa), Oenotherabiennis, Old man's beard, Usnea (Usnea spp.), Oregon grape root andbarberry (Mahonia spp.), Osha (Ligusticum porteri), Parsley(Petroselinum crispum), Passionflower (Passiflora incarnata), Peppermint(Mentha piperita), Plantain (Plantago spp.), Poplar buds (Populus spp.),Red clover (Trifolium pratense), Red raspberry (Rubus idaeus), Red root(Ceanothus americanus), Rhodiola Rosea, Rosemary (Rosmarinusofficinalis), Sage (Salvia officinalis), Saint John's wort (Hypericumperforatum), Saw palmetto (Serenoa repens), Sea-buckthorn (Hippophaerhamnoides), Sesame seed (Sesamum indicum), Siberian ginseng(Eleutherococcus senticosus), Skullcap (Scutellaria laterifolia),Slippery elm (Ulmus spp. (rubra, fulva)), Thyme (Thymus vulgaris),Triblus terrestris, Tumeric (Curcuma longa), Thuya occidentalis, Uvaursi (Arctostaphylos uva ursi), Valerian (Valeriana officinalis),Vervain (Verbena officinalis), White oak bark (Quercus alba), Wildcherry (Prunus spp.), Willow (Salix spp.), Yarrow (Achilleamillefolium), Yellow dock (Rumex crispus/obtusifolius), Yerba mate orcombinations thereof.

The active ingredient may also be specific natural compounds, includingwithout limitations Astaxanthin, Bilobalide, Biotine, Catechine,Choline, Coenzyme Q₁₀, Conjugated, Curcumine, Lecithin, linoleic acid,Ginkgolide, Glucosamine, Hypericine, Hyperforin, Silymarine, Silibinin,a Lignan, Diosgenine, hydroxycitric acid, eleutherocide B, EleutherocideE, L-carnitine, Leucine, Megastigmane glycoside, Melatonine,Niacinamide, Niacine, Omega-3, Pantothenic acid, a phytosterol,Phospholipids, Pinolenic acid, Resveratrol, Riboflavine, Rosiglitazone,Serotonin, Theobromine, Theophylline, Thiamine, g-aminobutyric acid(pathway), a saponin, sarsapic acid, Vitamin B₁₂, Yohimbine, gingerol,or combinations thereof.

The active ingredient may be chosen from Bilobalide, Ginkgolide,hypericine, hyperforin, Silymarine, Silibinin, a Lignan, Diosgenine,hydroxycitric acid, eleutherocide B, eleutherocide E, a phytosterol, asaponin, sarsapic acid, yohimbine, gingerol, or combinations thereof.

The phytosterol may be chosen from diosgenine, brassicasterol,campaestrol, 5α-cholestane, β-sitosterone, β-sitosterol, stigmasterol,or combinations thereof.

The active ingredient may be a Hypericum perforatum extract.

The active ingredient may be hypericine, hyperforin, or both.

The active ingredient may be a Hibiscus subdariffa extract.

The active ingredient may be a hydroxycitric acid.

The active ingredient may be an Eleutherococcus senticosus extract.

The active ingredient may be eleutherocide B, eleutherocide E, or both.

The active ingredient may be an Oenothera biennis extract.

The active ingredient may be a phytosterol chosen from diosgenine,brassicasterol, campaestrol, 5α-cholestane, β-sitosterone, β-sitosterol,stigmasterol, or combinations thereof.

The active ingredient may be a Silybum marianum extract.

The active ingredient may be Silymarine, Silibinin or both.

The active ingredient may be a Zingiber officinale extract.

The active ingredient is gingerol.

Uses and Methods

According to another embodiment of the present invention there isprovided therapeutic methods as described herein comprisingadministering a therapeutically effective amount of a dosage formaccording to the present invention.

According to another embodiment of the present invention dosage formaccording to the present invention are useful for therapeutic uses asdescribed herein.

The methods and uses include improving cognition, decreasing appetite,decreasing fatigue, reducing menstrual troubles, reducing hangover,reducing nausea, reducing nausea, reducing the stress, as an aphrodisiacor for pain relief.

According to another embodiment of the present invention there isprovided a method of improving cognition comprising administering atherapeutically effective amount of a dosage form according to thepresent invention.

According to another embodiment of the present invention there isprovided a method of decreasing appetite comprising administering atherapeutically effective amount of a dosage form according to thepresent invention.

According to another embodiment of the present invention there isprovided a method of decreasing fatigue comprising administering atherapeutically effective amount of a dosage form according to thepresent invention.

According to another embodiment of the present invention there isprovided a method of reducing menstrual troubles comprisingadministering a therapeutically effective amount of a dosage formaccording to the present invention.

According to another embodiment of the present invention there isprovided a method of reducing hangover comprising administering atherapeutically effective amount of a dosage form according to thepresent invention.

According to another embodiment of the present invention there isprovided a method of reducing nausea comprising administering atherapeutically effective amount of a dosage form according to thepresent invention.

According to another embodiment, of the present invention there isprovided a method for reducing nausea comprising administering atherapeutically effective amount of a dosage form according to thepresent invention.

According to another embodiment, of the present invention there isprovided a method for reducing stress comprising administering atherapeutically effective amount of a dosage form according to thepresent invention.

According to another embodiment, of the present invention there isprovided administering a therapeutically effective amount of a dosageform according to the present invention as an aphrodisiac.

According to another embodiment, of the present invention there isprovided administering a therapeutically effective amount of a dosageform according to the present invention for pain relief.

According to another embodiment of the present invention there isprovided a use of a dosage form according to the present invention forimproving cognition.

According to another embodiment of the present invention there isprovided a use of a dosage form according to the present invention fordecreasing appetite.

According to another embodiment of the present invention there isprovided a use of a dosage form according to the present invention fordecreasing fatigue.

According to another embodiment of the present invention there isprovided a use of a dosage form according to the present invention forreducing menstrual troubles.

According to another embodiment of the present invention there isprovided a use of a dosage form according to the present invention forreducing hangover.

According to another embodiment of the present invention there isprovided a use of a dosage form according to the present invention forreducing nausea.

According to another embodiment of the present invention there isprovided a use of a dosage form according to the present invention forthe preparation of a medicament for improving cognition.

According to another embodiment of the present invention there isprovided a use of a dosage form according to the present invention forthe preparation of a medicament for decreasing appetite.

According to another embodiment of the present invention there isprovided a use of a dosage form according to the present invention forthe preparation of a medicament for decreasing fatigue.

According to another embodiment of the present invention there isprovided a use of a dosage form according to the present invention forthe preparation of a medicament for reducing menstrual troubles.

According to another embodiment of the present invention there isprovided a use of a dosage form according to the present invention forthe preparation of a medicament for reducing hangover.

According to another embodiment of the present invention there isprovided a use of a dosage form according to the present invention forthe preparation of a medicament for reducing nausea.

In use, the oral dosages of the present invention may be employed forvarious therapeutic and/or nutraceutic improvements.

For example, Hypericum perforatum extract, and/or hypericine,hyperforin, or both may be used for improving cognition, or decreasingthe loss of cognition.

According to another embodiment, Hibiscus subdariffa extract and/orhydroxycitric acid may be used for decreasing appetite and weightcontrol.

According to another embodiment, Eleutherococcus senticosus extractand/or eleutherocide B, eleutherocide E, melatonine and polyphenol maybe used for decreasing fatigue.

According to another embodiment, the Oenothera biennis extract and/orphytosterol chosen from diosgenine, brassicasterol, campaestrol,5α-cholestane, β-sitosterone, β-sitosterol, stigmasterol, orcombinations thereof may be used for reducing menstrual troubles.

According to another embodiment, the Silybum marianum extract and/orSilymarine, Silibinin or both and also curcumin, choline, lecithin andHovenia dulcis may be used for reducing hangover.

According to another embodiment, the Zingiber officinale extract and/orgingerol and also Coenzyme Q₁₀, may be used for reducing nausea.

According to another embodiment, the melatonine, theanine and ginger teamay be used for reducing the stress.

According to another embodiment, Yohimbine may be used as anaphrodisiac.

According to another embodiment, the glucosamine may be used for painrelief.

The present invention will be more readily understood by referring tothe following examples which are given to illustrate the inventionrather than to limit its scope.

EXAMPLE I Preparation of a Functional Amalgam

Preparation of the Active Ingredient(s) Mixture

Dry powder form: plant parts (including root, bark, fruit, leaf, flower,stem, seed, rhizome, etc) are cut into small part and dried to obtain ahumidity factor of less than 15%. The dry parts are grinded to obtain afine powder.

Oil form (Oenothera biennis for example) are provided as cold-pressedextraction.

Reduction or elimination of complex sugar (cellulose, hemi-cellulose . .. ). Preparation of tinctures: A solution of about 15% to about 30% w/vof powdered dry plant parts and/or of the oil extract, in 70% ethanol isprepared and agitated for about 2 hours or more. The solution isfiltered through a filter or mesh and the remaining ethanol isevaporated by heating (79° C.) or by using a desiccator. Preparation ofa modulatory mixture comprising permeation enhancer and a modulator ofmelting point. To prepare the modulatory mixture, 95 g of coconut oil(containing 42-52% of lauric acid; melting point 25° C.) is mixed with 5g of Candelilla wax. The 95:5 modulatory mixture is melted at 75°-80° C.and mixed until an homogenous composition is obtained. As a function ofthe concentration of active ingredient and other constituents of thefinal mixture, the ratio of the modulatory mixture may differ to obtaina melting point of 36° C., the temperature of the mouth.

Preparation of CO₂-Sugar

CO₂-sugar is made by mixing ingredients including sugars, including forexample without limitations lactose (milk sugar), corn syrup, glucosesyrup, etc, or combinations thereof, and heating until they melt intodust, then exposing the mixture to pressurized carbon dioxide gas (about600 pounds per square inch; or approx. 41.37 Bar) and allowing thesugar/gas mixture to cool, thereby entrapping CO₂ gas therein. Theprocess causes tiny high pressure bubbles to be trapped inside thecandy. According to one embodiment of the present invention, theCO₂-sugar is prepared without any additional ingredient. According toanother embodiment of the present invention, the CO₂-sugar may also beprepared from a sugar composition to which one or more ingredients havebeen added. According to one embodiment, the ingredient may be one ormore of the active ingredients according to the present invention.

Preparation of the Functional Amalgam

50% of functional ingredient, 15% of CO₂-sugar, 10% of modulatorymixture, 24% of cellulose and 1% of lubricant.

Preparation of Functional Micro-Spheres

Pre-mix the active ingredient with cellulose and:

-   -   a) Dissolve the modulatory mixture in pre-heated alcohol        (denatured ethylic alcohol) at 55° C.;    -   b) Mix the active ingredient(s) with the cellulose        (microcrystalline Ph 100-200) in a commercial blender;    -   c) In the running blender, add the mix prepared in a);    -   d) Let the alcohol evaporate in an oven at 40° C.;    -   e) Sift the mixture through a 20 mesh sieve;    -   f) Add the CO₂-sugar to the mixture;    -   g) Add more cellulose to obtain a good flow;    -   h) Add the lubricant (stearate magnesium)

Composition Percentages

Modulatory mixture: up to 10%, (100% permeation enhancer/0 texturemodulator up to 90% permeation enhancer/10% texture modulator);

Cellulose: 10-40%

Active ingredient: up to 80%;CO₂-sugar: up to 20%,

Lubricant: up to 2%.

Furthermore, adhesives such as povidones (e.g. Polyvinylpyrrolidone)could also be included up to 3% and help the granulation process.

To obtain a free running preparation: Grind the sugar-CO₂ to obtainfragment of 1 mm or less and mix to the active ingredient. Pre-heat themodulatory mixture amalgam to 50° C., let it cool down to 40° C. and mixwith the previous mixture. Compressed the mixture in an multipunchtabletting machine to obtain micro-spheres of 35 mg (approximately 4-5mm in diameter). The compression force may be adjusted according to theactive ingredient liberation profile.

Preparation of Spheroids

As the starting material, the functional amalgam is used.

The powder is then extruded to form filaments of about 0.5 mm to 4 mm.The filaments are batched and dropped onto a spinning wheel where theyare fractured into short lengths. The speed, batch size, process timeare controlled to form spheres of specific sizes (from about 0.5 mm toabout 2 mm).

EXAMPLE II Preparation of Chewable Gel

Mix pure gelatin with water to a concentration of 14% w/v and heat themixture up to 50° C. with continuous stirring; once the mixture is fullyliquid, remove from heat and pour into mold to obtain a gel of 2-3 mmthickness. The gel is allowed to cool at room temperature for 10 minutesand plated at 4° C. for 10 minutes

The functional amalgam, on a powder form, is introduced directly withthe gelatin powder. The functional micro-spheres are introduced directlyin the gel during the cool-down step.

EXAMPLE III Chewing Gum

-   -   a) Base gum (chicle or butadiene, 49-80%, -styrene, 20-51%,        rubber blended with or substitute for poly-isobutylene+polyvinyl        acetate or isobutylene-isoprene) is heated at 120° C. (Warm both        pans for approximately 10 minute).    -   b) Remove the warmed base gum from oven and immediately make an        indentation in the gum base, add warmed wax and/or hydrogenated        vegetable oil (1-5%) and/or lecithin or glycerol monostearate        (1-5%) and/or coconut oil.    -   c) Mix thoroughly. Stabilized the base gum with BHT or BHA        (0.25-0.5%).    -   d) Rewarm the gum base to 120° C. for ten minutes.    -   e) Let cool down and add calcium carbonate or talc (5-20%) into        the softened base.    -   f) Rewarm at 120° C. for ten minutes.    -   g) During the cool down step, add Khlôros amalgam or functional        micro-spheres or spheroids.

EXAMPLE IV Liberation of Active Ingredient (Riboflavin)

Material:

Khlôros functional gel (see examples I and II);

0.9% Riboflavin;

Reactional media: 10 ml of H₂O/gel;

Passive liberation of active ingredient (Riboflavin): no treatment onthe gel;

Artificial mastication (active liberation): mimic the action ofmastication→compression and soft shearing;

Detection of the liberation of riboflavin and conversion in mM by thespectroscopic evaluation at 445 nm.

Comparison of Passive and Active Liberation of Riboflavin

After only 60 seconds, the liberation of riboflavin is 23 times moreeffective after artificial mastication compare to passive liberation(see FIG. 3).

Liberation of riboflavin from a functional gel made with microspheresriboflavin and powder riboflavin. Both gel contain 0.9% of riboflavin.The preparation of functional gel with Khlôros microspheres instead ofpowder riboflavin confer a liberation of active 7.7 times moreeffective, after 60 seconds of artificial mastication (see FIG. 4).

EXAMPLE V Evaluation of the Liberation of Active According to theArtificial Mastication Methods

The liberation of active ingredients from a complex preparation may beincreased with the proper gel. The material is a functional gel (seeexample II) with powder extract from Hibiscus sabdariffa flower (9%).

Artificial mastication methods. 2 methods were used to mimicmastication: 1° medium compression with soft shearing (see example III)and 2° medium compression with hard shearing (mimic the shearing byteeth).

Detection of the liberation of active ingredient from Hibiscus. Theabsorbance at 518 nm is measured by a spectrophotometer.

Using the Khlôros functional gel, compared to passive diffusion (nomastication) the liberation of actives is 12 times more efficient whenusing artificial mastication method 1, after 60 seconds. When usingmastication method 2, the liberation of actives is 20 times moreefficient compared to passive diffusion of actives (see FIG. 5).

EXAMPLE VI Comparison of the Mouth Absorption of Active(s) with andwithout Mastication Protocol

-   a. Weigh a fixed quantity of the Khlôros functional amalgam (with    50% of active);-   b. Ask the volunteer to clean his mouth with 10 ml of H₂O prior to    testing;-   c. Set the amalgam on the volunteer's tongue;-   d. The volunteer will have to chew or let the sample on his tongue    for a predetermined period of time (30 secs-60 secs-90 secs);-   e. The volunteer will have to avoid swallowing the sample;-   f. Collect saliva of the volunteer including the sample in a beaker;-   g. Ask the volunteer to rinse his mouth with 10 ml of H₂O (2×);-   h. Add H₂O to reach 30 ml and shake thoroughly.    As seen in FIG. 6, mastication allows absorption of active(s) by    oral mucosa up to 86% after only 90 seconds.

EXAMPLE VII Composition of Functional Chewing Gum

-   -   a. Gum base amalgam: gum base:isomalt (approximately 1:3)        70-85%;    -   b. Candelilla wax 0.5-5%    -   c. Lauric acid; <4%    -   d. CO₂ trapped sugar (CO₂ not from an acid and a carbonate        reaction); 3-20%;    -   e. Active ingredients: 0.5%-26%    -   All % are based on w/w.

EXAMPLE VIII Composition of Functional Chewing Gum

-   -   a. Gum base amalgam: gum base:isomalt (approximately 1:3)        70-85%;    -   b. Candelilla wax 0.5-5%    -   c. Lauric acid; <4%    -   d. CO₂ trapped sugar (CO₂ not from an acid and a carbonate        reaction); 3-20%;    -   e. *Menthol crystal; 1-5% or Could be *WS-3 0.5%;    -   f. * Flavor (e.g. Peppermint); 2.5%;    -   g. * Sweetener (e.g. Neotame); 0.0002-0.1%;    -   h. Active ingredients: 0.5%-26%    -   Ingredients marked with * in this example can be absent, present        or replaced. The % of the remaining ingredients would then be        adjusted accordingly.    -   All % are based on w/w.

EXAMPLE IX Composition of Functional Chewing Gum

-   -   a. Gum base amalgam: gum base:isomalt (approximately 1:3); 80%    -   b. Candelilla wax; 0.5%    -   c. Lauric acid; 3.0%    -   d. CO₂ trapped sugar (CO₂ not from an acid and a carbonate        reaction); 7.5%    -   e. *Menthol crystal; 2.5%;    -   f. *Peppermint flavor; 2.5%;    -   g. *Neotame as a sweetener; 0.0002%;    -   h. Active ingredients: 0.4%    -   Ingredients marked with * in this example can be absent, present        or replaced. The % of the remaining ingredients would then be        adjusted accordingly.    -   All % are based on w/w.

EXAMPLE X Functional Chewing Gum

-   -   a) Gum base amalgam: gum base: isomalt (approximately 1:3); 80%        (70-85%);    -   b) Candelilla wax; 1.0% (0.5-5%)    -   c) Phospholipids >60% (Phosphatidylcholine,        Phosphatidylethanolamine, Phosphatidylinositol, Phosphatidic        acid). 4% (<8%);    -   d) CO₂ trapped sugar (CO₂ not from an acid and a carbonate        reaction); 5% (<20%);    -   e) Menthol crystal/peppermint; 3.5%;    -   f) Sucralose 1.0%    -   g) Active ingredients: 5.5% of Angelica sinensis root extract    -   MCF: 4    -   All % are based on w/w.

Functional Chewing Gum 2

-   -   a) Gum base amalgam: gum base: isomalt (approximately 1:3); 80%        (70-85%);    -   b) Candelilla wax; 1.0% (0.5-5%)    -   c) Lauric acid; 3.0% (<4%)    -   d) CO₂ trapped sugar (CO₂ not from an acid and a carbonate        reaction); 5% (3-20%);    -   e) Menthol crystal/peppermint; 2.5% (1-5%);    -   f) Stevia 0.5%    -   g) Active ingredients: 8% of Colostrum    -   MCF: 4        All % are based on w/w.

EXAMPLE XI Natural Chewing Gum

-   -   a. Manilkara zapotilla (Chicle) 50% (30-70%);    -   b. Candelilla wax; 1.0% (0.1-5%);    -   c. Lauric acid; 3.0% (<4%);    -   d. CO₂ trapped sugar (CO₂ not from an acid and a carbonate        reaction); 5% (1-20%);    -   e. Menthol crystal; 2.0% (1-5%);    -   f. Peppermint flavor; 2.0%;    -   g. Sucralose 2.0%;    -   h. Mannitol 25%;    -   i. Active ingredient: Angelica sinensis root extract (10%).    -   MCF: 3    -   All % are based on w/w.        All ingredients are mix and compress to form a chewable amalgam.

EXAMPLE XII Active Chew Liberation in Function of Mastication Time

-   -   Preparation of Natural chewing gum (see Example XI) with Chicle        of 1.35 mm particle size (granulometry). The active is any        active as described herein (e.g. an extract of Hibiscus        Subdariffa);    -   Artificial mastication of one chew in 10 ml of water (or        artificial saliva; to be defined); Artificial mastication: use a        mortar/pestle corresponding to the buccal cavity, to mimic the        compression force on a standardize manner (force, temperature,        compression/minute . . . ).    -   The absorbance of the extruded liquid extract is analysed by        methods well known in the art (e.g for Hibiscus Subdariffa        spectrophotometer at 518 nm);    -   Time of mastication vary from 5 seconds to 30 seconds.    -   FIG. 8 shows that it is possible to vary the release of actives        from the dosage form. FIG. 8 also shows that there is a linear        relation between the liberation of active during the fast        release.

EXAMPLE XIII Liberation of Actives in Function of the Granulometry ofthe Chews

-   -   Preparation of Natural chewing gum (see Example XI) with Chicle        of different particle size (granulometry). The active is any        active as described herein (e.g. an extract of Hibiscus        Subdariffa); The size of the particles vary from 0.7 mm to 2 mm;    -   Artificial mastication of one chew in 10 ml of water (or        artificial saliva; to be defined). There are 3 mastication time:        10, 20 and 30 seconds;    -   The absorbance of the extruded liquid extract is analysed by        methods well known in the art (e.g for Hibiscus Subdariffa        spectrophotometer at 518 nm).    -   FIG. 9 shows that it is possible to vary the release of actives        from the dosage form with the particle size.

EXAMPLE XIV Sugar-CO₂ Variation of pH in Function of the Granulometry ofthe Sugar-CO₂

-   -   Prepare sugar-CO2 with different particle size: 0.5 mm to 2 mm;    -   Add 10% (w/v) of Sugar-CO₂ in 20 ml of agitated distilled water,        and note the decreased of pH with a pH meter;    -   Maximum pH decrease is 3 (at high particle size: 2 mm). Even at        very low particle size (0.7 mm), the decrease of pH is still        very high (2.3). See FIG. 7 a.

EXAMPLE XV Variation of pH in Function of the Concentration of Sugar CO₂

Add different concentration (0.2% to 15% w/v) of Sugar-CO₂ (particlesize of 1.35 mm) in 20 ml of agitated distilled water, note thedecreased of pH with a pH meter;

The variation of pH follow a logarithmic function (y=0.55 ln (x)+1.56);See FIG. 7 b.

EXAMPLE XVI Effect of Saliva on the Delivery of the Active by theChewable Vehicle

-   -   Chewing gums are prepared following example xx, containing a        bark extract of Corynanthe yohimbe (containing 8% of yohimbine);    -   Gums are artificially masticated for 120 seconds in 10 ml of        water or artificial saliva;    -   The quantity of released yohimbine is analysed by        chromatography.        The quantity of yohimbine released is more than 5 time when is        masticated in saliva than in water. The effect of bolus        (enzymes, texture . . . ) on the release of active is shown on        FIG. 10.

EXAMPLE XVII Absorption of Active(s) by Mouth Mucosa and Penetration inthe Blood

The absorption of active ingredients in the blood of a human volunteerwith a chewable vehicle of the invention can be determined by methodswell know in the art (Remington: The Science & Practice of Pharmacy 21thEdition, Lippincott Williams and Wilkins, Philadelphia, Pa. (2005)). Forexample, the active ingredient can be formulated in a chewableformulation (the “Active Chew”) according to the invention and given tohealthy volunteers. In order to determine the effect of mastication, onecan compare the blood levels of the active ingredient or a metabolitethereof following consumption of the chewable formulation when theActive Chew is masticated or simply swallowed.

In an other embodiment, instead of the measuring the blood level of theactive ingredient, the biological effect can be monitored followingadministration of the Active Chew.

In one embodiment, the following protocol can be followed to study theeffect of the chewable vehicle on the absorption of the activeingredient.

1) Cohort

6 volunteers age from 20 to 55 years old.

2) Chewable Material

Each chew ha san average of 2.0 g and comprises about 150 mg of activeextract mix or ingredients.

3) Administration Swallow the Gums

1 or 2 gums are cut in small pieces and swallow with water withoutchewing (control).

Chewing the Gums

The gums were chewed 10 minutes after the glucose load.

4) Blood Absorption

Measure of the blood levels or biological effect of active extract mixor ingredients according to methods well known in the art.

EXAMPLE XVIII Buccal Mucosa Absorption of Active Ingredient

Chewing gums are prepared following example VIII, containing an activeingredient as described herein. Gums are artificially masticated for 120seconds in 10 ml of artificial saliva. The quantity of released activeingredient is used in the EpiOral™ 3D-human buccal mucosa tissue.

EpiOral™ purchased from MatTek Corp. (Ashland, Mass.) is used for thoseexperiments. This model, a 3D-human buccal mucosa tissue, is an 8-11cell layered tissue consisting of an organized basal layer and multiplenon-cornified layers, with the characteristics of native buccal tissuedifferentiated from human primary oral keratinocytes.

On the day of treatments, 0.3 mL of EpiOral media warmed to 37° C. isdispensed into every well of a 24-weel plate. The EpiOral™ constructscultured on the surface of tissue inserts are transferred asepticallyinto the media filled 24 well plates. The tissues are then incubated at37° C. in a humidified atmosphere of 5% CO₂ for at least 1 hour. Theinserts are then transferred into a new 24-well plate containing 0.3 ofHank's buffered solution (HBSS).

The EpiOral™ tissue culture inserts are treated with test materials orartificial saliva and returned to the incubator. At specific timeintervals, the tissues are moved into a new 24-well plate. The receiversolution at each time point is kept for further analysis of the activeingredient content.

After 90 minutes of total permeation time, the tissue integrity ischecked.

Measurement of Active Ingredient Concentration

Active ingredient concentrations are measured by ultraperformance liquidchromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Thereceiver solutions are quantified without any dilutions. The massspectrometer is operated in MRM mode and an electrospray ionisationsource is used. The compound is retained 5 minutes in thechromatographic system and the transition 449>287 m/z is monitored inpositive mode.

Flux Calculation:

The amount (nmole) of active ingredient in each sample is converted tonmole/cm² assuming that the area of one EpiOral™ tissue is 0.6 cm².Cumulative nmole/cm² values are plotted as cumulative penetration(nmole/cm²) versus time where the slope of the linear regression is usedto calculate the steady state flux (J_(ss)).

In one aspect, the Khlôros vehicle contribute to accelerate the steadystate flux (absorption) compared to the active only in saliva.

While preferred embodiments have been described above and illustrated inthe accompanying drawings, it will be evident to those skilled in theart that modifications may be made without departing from thisdisclosure. Such modifications are considered as possible variantscomprised in the scope of the disclosure.

1.-73. (canceled)
 74. A composition for buccal mucosal absorption of apharmacologically active ingredient in a subject comprising: aparticulate amalgam matrix in the form of microspheres, spheres, orspheroids comprising: a hydrocolloid base in particulate form; thepharmacologically active ingredient in powder form; and crystallineparticles containing entrapped-CO₂ gas, wherein the particles have adiameter between about 0.5 mm and about 1 mm; wherein said chewablecomposition, is suitable for increasing the absorption of the activeingredient in the buccal mucosa by at least about 2× after being chewedfor 30 to 120 seconds as compared to a particulate composition devoid ofthe sugar particles and modulatory mixture.
 75. The composition of claim74, wherein the hydrocolloid base in particulate form is selected fromthe group consisting of agar, agarose, alginates, base gum, carrageenan(iota, kappa, lambda), cellulosics, chicle, chitosan, gelatin, gellangum, guar gum, gum arabic, locust bean gum, pectin, soybean gel, starch,whey protein, and xanthan gum.
 76. The composition of claim 75, whereinthe hydrocolloid base in particulate form is selected from the groupconsisting of base gum and chicle.
 77. The composition of claim 74,wherein the crystalline particles containing entrapped-gas comprisesCO₂-entrapped in sugar or menthol particles.
 78. The composition ofclaim 77, wherein the CO₂-entrapped sugar comprises popping sugar. 79.The composition of claim 74, further comprising a modulatory mixturecomprising: a) a permeation enhancer selected from the group consistingof sodium caprylate, sodium caprate, sodium laurate, lauric acid, oleicacid, lecithin, monoolein, phospholipids and acylcarnitines, andmixtures thereof; and b) a texture modulator selected from the groupconsisting of stearic acid, Candelilla and Carnauba wax, and mixturesthereof; wherein the permeation enhancer and the texture modulator arein a ratio suitable to achieve a melting point of about 36° C.
 80. Thecomposition of claim 74, wherein the composition is in particulate formand is compressed to form a chewable dosage form having a MatrixCohesive Force (MCF) between 2 and
 5. 81. The composition of claim 74,wherein the composition comprises 20% to 60% (w/w) of the amalgammatrix.
 82. The composition of claim 79, wherein the compositioncomprises from 0.5 to 15% (w/w) of the phospholipid and from 0.1 to 6%(w/w) of the wax.
 83. The composition of claim 76, wherein thecomposition comprises about 20% w/w to about 90% w/w of the particulategum base.
 84. The composition of claim 74, wherein the particulateamalgam matrix comprises particles having a size greater than about 0.9mm.
 85. The composition of claim 77, wherein the composition comprisesabout 5% w/w of the CO2-sugar particles.
 86. The delivery dosage form ofclaim 75, wherein the gum base comprises polyols.
 87. The composition ofclaim 74, wherein the active ingredient is selected from the groupconsisting of a) ion channel blockers, reflux suppressants,antiflatulents, antidopaminergics, proton pump inhibitors, H2-receptorantagonists, cytoprotectants, prostaglandin and prostaglandin analogues,laxatives, antispasmodics, antidiarrheals, bile acid sequestrants,opioids, beta-receptor blocker, diuretics, cardiac glycosides,antiarrhythmics, nitrate, antiangials, vasoconstrictor, vasodilators,peripheral activators, ACE inhibitors, angiotensin receptor blockers,alpha-blocker, anticoagulants, heparin, antiplatelet drugsfibrinolytics, anti-hemophilic factors, haemostatic drugs,hypolipidaemic agents, statins, hyphotics, anaesthetics, antipsychotics,antidepressants, antiemetics, anticonvulsants/antiepileptics,anxiolytics, barbiturates, folic acid, phenolic compounds, movementdisorder drugs, stimulants, benzodiazepine, cyclopyrrolones, dopamineagonists/antagonists, antihistamines, bromide, scopolamine,cholinergics, anticholinergics, emetics, cannabinoids, 5-HT antagonists,NSAIDs, opioids, paracetamol, muscle relaxant, neuromuscular drugs,anticholinesterases, adrenergic blockers, antibiotics, aminoglycosides,sulfa drugs, fluoroquinolones, antiviral drugs, anti-fungal,corticosteroids, mast cell inhibitors, prostaglandinagonists/inhibitors, steroids, steroids hormone receptor; antiseptics,anesthetics, androgens, antiandrogens, gonadotropin, human growthfactor, insulin, antidiabetics, thyroid hormones, antityroid drugs,calcitonin, diphosponate, vasopressin analogues, quinolones, 5-alphareductase inhibitor, selective alpha-1 blockers, sildenafils,tadalafils, fertility drugs, hormonal contraception, ormeloxifene,antifibrinolytics, follicle stimulating hormone, luteinising hormone,gamolenic acid, gonadotropin release inhibitor, progestin, oestrogen,gonadorelin, clomiphene, tamoxifen, diethyl stilbestrol, antileprotics,antituberculous drugs, antimalarials, anthelmintics, amoebicides,antivirals, antiprotozoals, vaccines, immunoglobulins,immunosuppressants, interferons, monoclonal antibodies, anti-allergics,cytotoxic drugs, therapeutic antibodies, somatostatin inhibitors,recombinant interleukins, G-CSF, erythropoietin, vitamins, antioxidantsand combinations thereof; b) Astaxanthin, Bilobalide, Biotine,Catechine, Choline, Coenzyme Q10, Curcumine, Ginkgolide, Glucosamine,Hypericine, Hyperforin, Silymarine, Silibinin, a Lignan, Diosgenine,hydroxycitric acid, eleutherocide B, Eleutherocide E, L-carnitine,Megastigmane glycoside, Melatonin, Niacinamide, Niacine, Omega-3,Pantothenic acid, a phytosterol, Pinolenic acid, Resveratrol,Riboflavine, Rosiglitazone, Serotonin, Theobromine, Theophylline,Thiamine, g-aminobutyric acid, a saponin, sarsapic acid, Vitamin B12,Yohimbine, gingerol, or combinations thereof; or c) a plant extractselected from the group consisting of Absinthe (Artemisia absinthum),Alfalfa (Medicago sativa), Aloe (Aloe barbadensis), Angelica (Angelicaarchangelica and sinensis), Arnica (Arnica montana), Ashwaganda(Withania somnifera), Astragalus (Astragalus membranaceus), Betony(Stachys/Betonica officinalis), Bilberry/Huckleberry (Vaccinium spp.),Black cohash (Cimicifuga racemosa), Bladderwrack (Fucus versiculosus),Blessed thistle (Cnicus benedictus), Blue cohosh (Caulophyllumthalictroides), Boneset (Eupatorium perforatum), Burdock (Arctiumlappa), Caesalpinia benthamiana, Calendula (Calendula officinalis),California poppy (Eschscholzia californica), Caraway (Carum carvi),Cardamom (Elettaria cardamomum), Cascara (Rhamnus purshiana), Catnip(Nepeta cataria), Cayenne (Capsicum frutescens), Cedar, Western (Thujaplicata or occidentalis), Chamomile (Matricaria recutita), Chaparral(Larrea mexicana), Chaste tree berry (Vitex agnus castus), Chickweed(Stellaria media), Cleavers (Galium aparine), Coltsfoot (Tussilagofarfara), Comfrey (Symphytum officinalis), Corn silk (Zea mays),Corynanthe yohimbe, Cramp bark (Viburnum opulus), Dandelion (Taraxacumofficinalis), Devil's club (Oplopanax horridus), Dioscorea villosa, Dongquai (Angelica sinensis), Echinacea (Echinacea spp.), Elder flowers(Sambucus spp.), Elecampane (Inula helenium), Eyebright (Euphrasiaofficinalis), Fadogia agrestis, Fennel (Foeniculum vulgare), Fenugreek(Trigonella foenum-graecum), Feverfew (Tanacetum parthenium), Flax seed(Linum usitatissimum), Garcinia Cambogia, Garlic (Allium sativa),Geranium (Geranium maculatum), Ginger (Zingiber officinalis), Ginkgo(Ginkgo biloba), Ginseng (Panax spp.), Goldenrod (Solidago spp.),Goldenseal (Hydrastis canadensis), Gotu kola (Centella asiatica), Gravelroot (Eupatorium purpureum), Hawthorne (Crataegus spp.), Hibiscussubdariffa, Hops (Humulus lupulus), Horehound (Marrubium vulgaris),Horsetail (Equisetum arvense), Hippophae rhamnoides, Hyssop (Hyssopusofficinalis), Kava kava (Piper methysticum), Lady's mantle (Alchemillavulgaris), Lepidium meyenii, Linden flower (Tilia spp.), Lobelia(Lobelia inflata), Lomatium (Lomatium dissectum), Lungwort (Stictapulmonaria), Marshmallow (Althea officinalis), Massularia acuminate,Meadowsweet (Filipendula ulmaria), Microdesmis keayana, Milk thistle(Silybum marianum), Morinda citrifolia, Motherwort (Leonurus cardiaca),Mucuna pruriens, Mugwort (Artemisia vulgaris), Mullein (Verbascumthapsus), Myrrh gum (Commiphora myrrha), Nettle (Urtica spp.), Noni(Morinda citrifolia), Nopal (Opuntia ficus indica), Oat (Avena sativa),Oenothera biennis, Old man's beard, Usnea (Usnea spp.), Oregon graperoot and barberry (Mahonia spp.), Osha (Ligusticum porteri), Parsley(Petroselinum crispum), Plantain (Plantago spp.), Poplar buds (Populusspp.), Red clover (Trifolium pratense), Red root (Ceanothus americanus),Rhodiola Rosea, Rosemary (Rosmarinus officinalis), Sage (Salviaofficinalis), Saint John's wort (Hypericum perforatum), Saw palmetto(Serenoa repens), Sea-buckthorn (Hippophae rhamnoides), Sesame seed(Sesamum indicum), Siberian ginseng (Eleutherococcus senticosus),Skullcap (Scutellaria laterifolia), Slippery elm (Ulmus spp. (rubra,fulva)), Thyme (Thymus vulgaris), Triblus terrestris, Tumeric (Curcumalonga), Thuya occidentalis, Uva ursi (Arctostaphylos uva ursi), Valerian(Valeriana officinalis), Vervain (Verbena officinalis), White oak bark(Quercus alba), Willow (Salix spp.), Yarrow (Achillea millefolium),Yellow dock (Rumex crispus/obtusifolius) and Guaraná, and combinationsthereof.
 88. The composition of claim 87, wherein the active ingredientis selected from the group consisting of Guaraná, Black cohash(Cimicifuga racemosa), Ginseng (Panax spp.), Hops (Humulus lupulus),Rhodiola Rosea, Tumeric (Curcuma longa), Astaxanthin, Coenzyme Q₁₀,Curcumine, Glucosamine, Melatonin, Resveratrol, gingerol, diosgenine,bras sicasterol, campesterol, 5α-cholestane, β-sitosterone, β-sitosteroland stigmasterol, and combinations thereof.
 89. The composition of claim87, wherein the active ingredient is selected from the group consistingof NSAIDs; Beta-receptor blockers; Vasodilators; Antiarrhytmics;Antibiotics; Ion channel blockers; Antispasmodics; Anaesthetics;Diphosphonates; Diuretics; Stimulants; Antihistamines;Angiotensin-Converting Enzyme (ACE) Inhibitors; Antiviral drugs;Antiemetics; Vasoconstrictors; Dopamine agonists/antagonists; Protonpump inhibitors; Antidiabetics; H2 receptor antagonists;Antidepressants; 5-HT antagonists; Anxiolytics; Hypnotics; Musclerelaxants; Anticholinergics; Somatostatine inhibitors; Antioxidants;Angiotensin receptor blockers; Steroids hormone receptor; Oestrogens;and Statins; and combination thereof.
 90. The composition of claim 89,wherein the stimulant is caffeine.
 91. The composition of claim 87,wherein the active ingredient is Rodiola Rosea.
 92. The composition ofclaim 87, wherein the active ingredient is melatonin.